Aim: To examine whether a novel endothelin receptor antagonist, CPU0213, is effective in relieving the acute renal failure (ARF) of septic shock by suppressing the activated endothelin-reactive oxygen species (ET-ROS) pathway and nuclear factor kappa B (NF-κB). Methods: The cecum was ligated and punctured in rats under anesthesia. CPU0213 (30 mg·kg-1·d-1, bid, sc×3 d) was administered 8 h after surgical operation. Results: In the untreated septic shock group, the mean arterial pressure and survival rate were markedly decreased (P＜0.01), and heart rate, weight index of kidney, serum creatinine and blood urea nitrogen, 24 h urinary protein and creatinine were significantly increased (P＜0.01). The levels of ET-1, total NO synthetase (tNOS), indusible nitric oxide synthetase (iNOS), nitric oxide (NO), and ROS in serum and the renal cortex were markedly increased (P＜ 0.01). The upregulation of the mRNAlevels of preproET-1, endothelin converting enzyme, ETA, ETB, iNOS, and tumor necrosis factor-alpha in the renal cortex was significant (P＜0.01). The protein amount of activated NF-κB was significantly increased (P＜0.01) in comparison with the sham operation group. All of these changes were significantly reversed after CPU0213 administration. Conclusion: Upregulation of the ET signaling pathway and NF-κB play an important role in the ARF of septic shock. Amelioration of renal lesions was achieved by suppressing the ETA and ETB receptors in the renal cortex following CPU0213 medication.